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P655. Gene expression alterations suggest that ulcerative colitis patients after restorative proctocolectomy have ileal disease

H. Yanai1, S. Ben-Shachar2, L. Baram1, H. Elad1, A. Ofer1, G. Gitstein3, E. Brazowski3, H. Tulchinsky4, M. Pasmanik-Chor5, I. Dotan1, 1Tel Aviv Sourasky Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, IBD Center, Department of Gastroenterology and Liver Diseases, Tel Aviv, Israel, 2Tel Aviv Sourasky Medical Center affiliated to Sackler Faculty of Medicine, Tel Aviv university, Genetic institute, Tel Aviv, Israel, 3Tel Aviv Sourasky Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, Department of Pathology, Tel Aviv, Israel, 4Tel Aviv Sourasky Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, Proctology Unit, Department of Surgery, Tel Aviv, Israel, 5Tel Aviv University, Tel Aviv, Israel, Bioinformatics unit, G.S.W. Faculty of Life Sciences, Tel Aviv, Israel

Background

Pouchitis is the inflammation developing in a normal small bowel reservoir (pouch) created in ulcerative colitis (UC) patients undergoing restorative proctocolectomy. The aetiology of pouchitis is unknown. The endoscopic and histologic inflammation is limited to the pouch, while the proximal ileum is generally not affected. We previously showed that gene expression alterations in pouchitis are associated with disease behaviour. We aimed to evaluate molecular characteristics of the ileum proximal to the pouch.

Methods

UC patients after pouch surgery were prospectively recruited, and stratified according to disease behaviour into normal pouch (NP), chronic pouchitis (CP), and Crohn's-like disease of the pouch (CLDP) subgroups. Ileal biopsies were obtained from the pouch as well as the normal appearing proximal ileum (40 cm proximal to the anal verge), and compared to ileal biopsies from normal controls (NC). A histopathological score was created based on the degree of active (polymorphonuclear) and chronic (mononuclear) infiltrates (1-normal, 5-massive infiltrate). Gene expression analysis was performed using microarrays, and validated by real-time PCR. Gene ontology and clustering were evaluated using bioinformatic tools.

Results

Thirty-six subjects [7 NP, 15 pouchitis (10 CP, 5 CLDP) and 14 NC] were recruited. Significant differences of histopathology scores within the pouch were noticed: median activity scores: 1/5 NP, 2/5 CP, 4/5 CLDP (P = 0.001), median chronicity scores 2/5 NP, 3/5 CP, 3/5 CLDP (P = 0.015). Histopathological differences in the proximal ileum were less pronounced. Nonetheless, significant (fold change ≥2, corrected P ≤ 0.05) molecular alterations were detected in the normal appearing proximal ileum of all pouch groups compared with NC: NP (n = 9), CP (n = 80) and CLDP (n = 230). DUOX2 alteration magnitude in the proximal ileum was highest: an increase of 6.0, 9.8 and 21.7 fold change in NP, CP, CLDP respectively, followed by MMP1 and SLC6A14. Moreover, gene alterations in the proximal ileum overlapped with those observed within the pouch: 76% and 97% overlap in CP and CLDP, respectively. Gene ontology analysis for proximal ileal alterations revealed association with multiple biological processes including active and anion transmembrane transporter activity and metallopeptidase activity.

Conclusion

Significant gene expression alterations were detected not only within pouches, but also in the proximal ileum. Alterations in the pouch and the proximal ileum were comparable. These findings may suggest that the inflammatory processes occurring in pouch patients are not limited to the surgically manipulated region (the pouch) but rather extend to the proximal ileum, potentially exposing it to further inflammation.